DE3423105A1 - METHOD FOR PRODUCING OPTICALLY ACTIVE 1,4-DIHYDROPYRIDINE - Google Patents

Abstract

<IMAGE> +TR <IMAGE> <IMAGE> in which optically pure products are obtained. The process is novel, as is II. I is known as being active on the blood circulation system.

Description

BAYER AKTIENGESELLSCHAFT 5090 Leverkusen, Bayerwerk

Group administration RP KS / by-c «η ¹ MiYl Patent Department IV (Pha) ^{c υ} "'''

Process for the preparation of optically active 1,4-dihydropyridines

The present invention relates to a novel process for the preparation of optically active 1,4-dihydropyridine derivatives.

It is already known that certain 1,4-dihydropyridine derivatives have interesting pharmacological properties and in particular as influencing the circulation Funds are used (see F. Bossert and W. Vater, Naturwissenschaften 5jJ, 578 (1971) and DE-OS 21 17 571).

Furthermore, it is already known that the antipodes are chiral 1,4-dihydropyridine-3,5-dicarboxylic acid esters can be represented by various methods (DE-OS 29 35 451; T. Shibanuma et al. Chem. Pharm. Bull. 28., 2809 (1980); DE-OS 33 20 616).

The present invention is a new, chemically peculiar process for the preparation of

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2T-

■ 43-

optical antipodes of chiral 1,4-dihydropyridine-3,5 dicarboxylic acid diester.

It has been found that the partially known antipodes of chiral 1,4-dihydropyridine dicarboxylic acid esters can be used of the general formula (I),

(D

in which

R for carbocyclic aryl or for heterocycles from the group consisting of thienyl, furyl, pyrryl, pyrazolyl, Imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, Indolyl, benzimidazolyl, benzoxazolyl, benzoxadiazolyl, benzthiadiazolyl, quinolyl, isoquinolyl, Quinazolyl or quinoxalyl, the aryl radical and the heterocycles optionally 1 to 3 identical or different substituents from the group phenyl, alkyl, alkoxy, alkylene, dioxyalkylene, Halogen, polyfluoroalkyl, polyfluoroalkoxy, Contain alkylamino, nitro, cyano, azido, alkoxycarbonyl or SO -alkyl (m = 0 to 2),

R and R are always different and represent an achiral straight-chain, branched or cyclic, saturated one or unsaturated hydrocarbon

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remaining, which may be replaced by an oxygen or sulfur atom in the chain is interrupted, and / or which is optionally substituted is represented by halogen, cyano, alkoxycarbonyl, phenyl, phenoxy, phenylthio or phenylsulfonyl where the phenyl groups in turn can be substituted by halogen, cyano, dialkylamino, Alkoxy, alkyl, trifluoromethyl or nitro, or where the hydrocarbon radical is substituted can be by pyridyl or an amino group, this amino group by two identical or various substituents from the group consisting of alkyl, alkoxyalkyl, aryl or aralkyl is substituted, or wherein the amino group is substituted in such a way that two substituents together with the nitrogen atom form a 5- to 7-membered ring, the other heteroatom is oxygen or sulfur or an N-alkyl / phenyl group may contain

4th

R and R can be identical or different and each represents hydrogen, an achiral straight-chain or branched, optionally substituted alkyl radical, an aryl radical or a Aralkyl radical

and

R represents hydrogen or an achiral straight-chain or branched alkyl radical, an aryl radical or

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represents an aralkyl radical,

obtained when the compounds of the general formula (II) (including their prototropic forms)

^r1 0 ₂ Cv ^ \ ^ C0 ₂ R ⁵ R ² NR ⁴

R3

¹¹

12 4 5

in which the radicals R, R, R, R and R have the meaning given above and R is an alkyl or aralkyl radical and in which the configuration at the carbon atoms marked with (*) is uniformly defined is,

with amines of the general formula (III)

R ³ -NH ₂ (III)

or their acid addition salts,
in which R has the meaning given above,

optionally reacting in the presence of suitable solvents.

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A major advantage of the process is that it is due to its simple reaction conditions can be carried out with little technical effort and high economic efficiency, with particular It should be pointed out that in the reaction (S) - or (R) -1-amino-2-alk (aralk) oxymethyl-pyrrolidine is released again and can be reintroduced into the reaction process as a chiral inductor.

The preparation of an optically active 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid Ethyl isopropyl ester can be exemplified by the following Formula scheme can be reproduced:

O ₂ C ^ k CO ₂ C ₂ H ₅

N ^CH3 H

The process according to the invention gives an optically active 1,4-dihydropyridine derivative of the general type Formula (I) by reaction of an optically active, uniformly configured hydrazone of the general

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mean formula (II) with an amine or its acid addition salt of the general formula (III), if appropriate in the presence of a suitable solvent.

In the formulas (I) and (II) preferably stands

R stands for a phenyl or naphthyl radical or for thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, Oxazolyl / isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, indolyl, Benzimidazolyl, Benzoxazolyl, Benzisoxazolyl, Benzoxadiazolyl, Benzthiadiazolyl, Quinolyl, Isoquinolyl, quinazolyl or quinoxalyl, the said heterocycles and the phenyl radical and the naphthyl radical 1 to 3 can carry identical or different substituents, where as Substituents phenyl, straight-chain or branched alkyl with up to 8 carbon atoms, Cycloalkyl with 3 to 7 carbon atoms, alkenyl or alkynyl with 2 to 6 carbon atoms, Alkoxy with 1 to 4 carbon atoms, alkenoxy and alkynoxy with 2 to 6 carbon atoms, Tri-, tetra- and pentamethylene, dioxymethylene, dioxyethylidene, halogen such as fluorine, Chlorine, bromine or iodine, trifluoromethyl, trifluoroethyl, Trifluoromethoxy, difluoromethoxy, tetrafluoroethoxy, Dialkylamino with 1 to 4 carbon atoms, nitro, cyano, azido, alkoxycarbonyl with 1 to C atoms in the alkoxy radical or SO -alkyl, in which m is 0 or 2 and alkyl is 1 to 4 carbon atoms contains.

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• AS-

Furthermore, in the formulas (I) and (II) are preferred

5
R and R, which are always different, represent an achiral straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical with up to 8 carbon atoms, which is optionally interrupted by an oxygen or sulfur atom in the chain and / or which is optionally substituted by Halogen such as fluorine or chlorine, cyano, alkoxycarbonyl with up to 4 carbon atoms in the alkyl part, phenyl, phenoxy, phenylthio or phenylsulfonyl, whereby the phenyl groups in turn can be substituted by halogen such as fluorine or chlorine, cyano, dialkylamino with up to 4 carbon atoms per alkyl group, Alkoxy or alkyl, each with up to 4 carbon atoms, trifluoromethyl or nitro, or where the hydrocarbon radical can be substituted by pyridyl or an amino group, this amino group being replaced by two identical or different substituents from the group consisting of alkyl with up to 4 carbon atoms, alkoxyalkyl with up to 6 carbon atoms, aryl, in especially phenyl, or aralkyl, especially benzyl, is substituted, or where the amino group is substituted in such a way that two radicals together with the nitrogen atom form a 5- to 7-membered heterocyclic ring, the further heteroatom is oxygen

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A9-

or sulfur or an N-alkyl / phenyl group may contain

and

2 4
R and R, which can be identical or different, represent hydrogen or, preferably, a straight-chain or branched, optionally substituted alkyl radical with up to 4 carbon atoms, a phenyl or a benzyl radical.

Furthermore, in formula II, R preferably represents an achiral straight-chain or branched alkyl radical with up to 4 carbon atoms, in particular for the methyl group, or for an aralkyl radical, in particular for the benzyl radical.

The compounds of the general formula (II) are new and can, in analogy to processes known from the literature, by addition of an optically active hydrazone of the (S) - or (R) -1-amino-2-alk (aralk) oxymethyl-pyrrolidines of the general formula (IV) including its prototropic forms to stereochemically uniform

.CO ₂ R ¹

R-CH = C-R ⁴ -C-CH ₂ -CO ₂ R ⁵

^N COR ² "

N V

OR ⁶

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prochiral ylidene-ß-ketocarboxylic acid esters of the general Formula (V) can be obtained (cf. D. Enders and K. Papdopoulos, Tetrahedron Letters 24 '4967 (1983)). In the formulas (IV) and (V) the radicals R, R, R, R, R and R have the meanings given above.

In the formulas (I) and (III) stands

R preferably represents hydrogen or an achiral straight-chain or branched alkyl radical with up to to 4 carbon atoms / a phenyl radical or a benzyl radical.

The amines of the formula (III) or their acid addition salts used as starting compounds are known. As acid addition salts, the salts come from both inorganic and organic acids in question, whereby hydrohalic acids, sulfuric acid, Carbonic acid and acetic acid may be mentioned by way of example.

Ammonium and methylammonium sulfates, chlorides, carbonates, hydrogen carbonates and acetates may be mentioned in particular and oxalates.

All inert organic solvents can be used as diluents. These preferably include Alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, glycol monomethyl ether or Glycol dimethyl ether, glacial acetic acid, dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine or hexamethylphosphoric acid triamide.

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The reaction temperatures can be varied over a wide range. In general, the temperature is between 0 and 150 ^° C., preferably between 20 and 100 ^° C., in particular at the boiling point of the particular solvent.

The reaction can be carried out under normal pressure, but also under increased pressure. Generally works one under normal pressure.

When carrying out the method according to the invention 1 mole of the hydrazone of the general formula (II) with 1 to 5 moles of the amine of the general formula (III) or its acid addition salt reacted in a suitable solvent.

The isolation and purification of the end products is preferably carried out in such a way that the solvent in Distilled off in vacuo and the residue, if appropriate, the purification operations known from the prior art, such as recrystallization from a suitable one Solvent or subjected to chromatographic separation.

The method according to the invention is suitable for representation of the optical antipodes of chiral 1,4-dihydropyridine-3,5-dicarboxylic acid diesters with a wide range of substituents and structural variations.

In addition to the preparation examples given below, the enantiomers of the following active ingredients are special mentioned:

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1,4-dihydro-2,6-dimethyl-4- {3-nitrophenyl) pyridine-3,5-dicarboxylic acid isobutyl methyl ester,

1,4-Dihydro-2,6 ~ dimethyl-4- (3-nitrophenyl) -pyridine-3, S-dicarboxylic acid methyl neopentyl ester,

1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3, S-dicarboxylic acid cyclopentyl methyl ester,

1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid isopropyl (2-methoxyethyl) ester,

1, 4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid-methy1- (2-N-benzyl-N-methylamino-ethyl) ester,

1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid methyl (2- (4-phenyl-piperazinyl-1) ethyl) ester,

1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -pyridine-3,5-dicarboxylic acid-benzy1-methyl-ester,

1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) pyridine-3,5-dicarboxylic acid methyl (2-phenoxyethyl) ester,

1,4-dihydro-2,6-dimethyl-4- (2-trifluoromethylpheny1) -pyridine-3,5-dicarboxylic acid isopropyl methyl ester,

1,4-Dihydro-2,6-dimethyl-4- {2-chlorophenyl) -pyridine-3,5-dicarboxylic acid-allyl-methyl-ester,

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1,4-dihydro-2,6-dimethyl-4- (2,3-dichlorophenyl) -pyridine-3,5-dicarboxylic acid ethyl methyl ester,

1 ^ -Di

3,5-dicarboxylic acid hexyl methyl ester,

1,4-dihydro-2,6-dimethyl-4- (2-chlorophenyl) pyridine-3,5-dicarboxylic acid methyl (2,2,2-trifluoroethyl) ester,

^ - (2-Chlorophenyl) -pyridine-3,5-dicarboxylic acid-ethy 1- (2,2,2-tr if luoroethyl) ester,

1,4-dihydro-2,6-dimethyl-4- (2-cyanophenyl) -pyridine-3,5-dicarboxylic acid ethyl-methyl-ester,

1,4-dihydro-2,6-dimethyl-4- (pyridyl-3) -pyridine-3,5-dicarboxylic acid ethyl methyl ester,

^ - (pyridyl-2) -pyridine-2,5-dicarboxylic acid-cyclohexyl-methyl-ester,

-j _f 4-dihydro-2,6-dimethyl-4- (2,1, 3-benzoxadiazolyl-4) pyridine-3,5-dicarboxylic acid isopropyl methyl ester,

1,4-dihydro-2,6-dimethyl-4- (2,1,3-benzoxadiazolyl-4) -pyridine-3,5-dicarboxylic acid ethyl methyl ester,

1,4-dihydro-i, 2,6-trimethyl-4- (2,1,3-benzoxadiazolyl-4) pyridine-3,5-dicarboxylic acid isopropyl methyl ester,

1,4-dihydro-1,2,6-trimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid ethyl-methyl-ester,

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1,4-Dihydro-1,2,6-trimethyl-4- (2-nitrophenyl) -pyridine-3,5-dicarboxylic acid, isobutyl-methyl-ester.

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Manufacturing examples example 1

(-) 1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid ethyl methyl ester

HsC ₂ O ₂ C yA ^ CO ₂ CH ₃

To a solution of 10 g (43.8 mmol) of (S) -3- / T2-Methoxymethyl-pyrrolidin-1-yl) -imino7-methyl butyrate in 90 ml of absolute tetrahydrofuran were added after the addition of 25 ml Tetramethylethylendxamin at -70 ⁰ C and under 28 ml (44.8 mmol) of a 1.6 molar BuLi solution in η-hexane were added dropwise to nitrogen. A solution of 11.5 g (43.8 mmol) was then 2- (3-nitrobenzylidene) -acetessig acid ethyl ester are added dropwise in 75 ml of tetrahydrofuran at -70 ⁰ C. After stirring at -70 ⁰ C, the cooling bath was removed, the reaction solution is left to reach room temperature by itself (about 3 to 4 hours) and then carefully poured into ether / water. The aqueous phase was extracted again with ether and, after drying over anhydrous sodium sulfate, the combined ethereal extracts were concentrated in vacuo, an oily residue (15 g, M = 491) resulting, which was chromatographically

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-SG

was cleaned. 12g (24mmol) of this intermediate were taken up in 50 ml of methanol and after adding 3.2 g (60 mmol) of ammonium chloride for 15 hours Boiling heated. The solvent was then distilled off in vacuo, the residue in dichloromethane taken up and washed with water. After drying over NaSO. constricted. That residual oil partially crystallized after trituration with ether, the crude product was filtered off with suction, washed with ether and dried, 3.3 g (38%) mp: 159 ° C.

= -14.97 ° (C = 0.57%, ethanol).

Example 2

NO ₂

Analogously to Example 1, using the (R) -3- / 72-methoxymethylpyrrolidin-i-yl) -imino7-butyric acid methyl ester the clockwise 1,4-dihyäro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid ethyl methyl ester obtain.

Mp: 160 ° C,

⁼ +15.56 (C = 0.41%, ethanol)

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Example 3

(-) 1 ^ -Dihydro- ^ fe-cLimethyl-'l- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid -isopropyl-methyl-ester

, .NO ₂

O ₂ C _v J ^ CO ₂ CH ₃

H ₃ CN CH ₃

H
To a solution of 7.1 g (31 mmol) of (S) -3- / T2-Methoxymethyl-pyrrolidin-1-yl) -imino7-methyl butyrate in 60 ml of absolute tetrahydrofuran were added after addition of 20 ml tetramethyl ethylene diamine at -70 ⁰ C. and 20 ml (32 mmol) of a 1.6 molar solution of butyllithium in η-hexane are added dropwise under nitrogen. A solution of 8.6 g (31 mmol) was then 2- (3-nitrobenzylidene) was added dropwise -acetessigsäureisopropylester in 40 ml of tetrahydrofuran at -70 ⁰ C. The reaction mixture was stirred for 1 hour at -70 ⁰ C, then the cooling bath was removed, and after reaching room temperature (approximately 3 to 4 hours) the solution was poured slowly into ether / water. The aqueous phase was extracted several times with ether and the combined organic extracts were dried over anhydrous sodium sulfate. Evaporation of the solvent in vacuo gave an oily one

Intermediate product (12 g, M = 505) which was purified by chromatography. 8g (15.8mmol) of this Compound were dissolved in 50 ml of methanol and after

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- "." jig.

Addition of 3.4 g (64 mmol) ammonium chloride for 16 hours heated to reflux. The solvent was distilled off in vacuo, the residue in dichloromethane taken up and washed with water. The organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo and the oily residue caused to crystallize by trituration with a little ether. The solid product was filtered off with suction and dried, 2.3 g (39%), melting point: 136.degree

CcOJ ^ ⁼ -24.60 ° (C = 1.07%, ethanol). Example 4

NO ₂

° ' ^C ^ J ^ ^ CO ₂ CH-

H ₃ C "Ν CH ₃
H

Analogously to Example 3, using the (R) -3- / 72-methoxymethylpyrrolidon-1-yl) -iminoy-butyric acid methyl ester, the dextrorotatory 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine- ^ S-dicarboxylic acid isopropyl methyl ester obtained.
M.p .: 136 ° C

1 ~ ° 0Jq ° = + 24.97 ° (C = 0.93%, ethanol).

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- w --Ä9-

Example 5

(-) 1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) -pyridine-3,5-dicarboxylic acid isobutyl-methyl-ester

H ₃ C

H ₃ CN CH ₃

To a solution of 7.1 g (31 mmol) of (S) -3- / 72-Methoxymethyl-pyrrolidin-1-yl) -iminoy-buttersauremethylester in 60 ml of absolute tetrahydrofuran were added after addition of 20 ml of tetramethylethylenediamine at -70 ⁰ C and under 20 ml (32 mmol) of a 1.6 molar solution of butyllithium in η-hexane were added dropwise to nitrogen. A solution of 9 g (31 mmol) was then stored at -70 ⁰ C 2- (2-nitrobenzylidene) -acetessigsäureisobutylester added dropwise in 50 ml of tetrahydrofuran and the solution stirred for a further 1 hour at -70 ^0C. The cooling bath was removed and upon reaching

-j5 from room temperature (about 3 to 4 hours) was the Solution slowly poured into ether / water. The aqueous phase was extracted again with ether and the combined organic extracts dried over anhydrous sodium sulfate. Distilling off the solvent under vacuum gave an oily intermediate (12.8 g, M = / 519) which was chromatographed on Silica gel has been purified.

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6.4 g (12.3 mmol) of this compound were in 25 ml Dissolved methanol and, after the addition of 1.61 g (30.2 mmol) of ammonium chloride, heated under reflux for 15 hours. The solvent was distilled off in vacuo, the residue was taken up in dichloromethane and washed with water washed. The organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo and the oily residue is purified by chromatography, 1.4 g (30%) of amorphous product.

⁼ -I ^{66 '40' 0 '49%} w / v. Ethanol).

Example 6

H ₃ C

H ₃ C

HC-H ₂ CO ₂ C

H ₃ C

CH ₃

Analogously to Example 5, using the (R) -3- / 72-methoxymethylpyrrolidin-1-yl) -iminoy-butyric acid methyl ester the dextrorotatory 1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -pyridine-3,5-dicarboxylic acid-isobutyl-methyl ester obtain.

⁼ + 166.3 ° (0.68% w / v, ethanol).

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Claims (9)

Claims 1. Process for the preparation of chiral antipodes 1/4-dihydropyridine dicarboxylic acid ester of the general Formula (I), in which R for carbocyclic aryl or for heterocycles from the group thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, Pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, Indolyl, benzimidazolyl, benzoxazolyl, benzoxadiazolyl, Benzthiadiazolyl, quinolyl, isoquinolyl, quinazolyl or quinoxalyl, where the aryl radical and the heterocycles, optionally 1 to 3 identical or different Substituents from the group phenyl, alkyl, alkoxy, alkylene, dioxyalkylene, halogen, polyfluoroalkyl, Polyfluoroalkoxy, alkylamino, nitro, cyano, azido, alkoxycarbonyl or SO-alkyl (m = 0 to 2) included. Le A 23 151 5
R and R are always different and represent an achiral straight-chain, branched or cyclic / saturated or unsaturated hydrocarbon radical, which is optionally replaced by an oxygen or sulfur atom in the Chain is interrupted, and / or which is optionally substituted by halogen, cyano, alkoxycarbonyl, Phenyl, phenoxy, phenylthio or phenylsulfonyl, the phenyl groups in turn being substituted can be through halogen, cyano, dialkyl- amino, alkoxy, alkyl, trifluoromethyl or nitro, or where the hydrocarbon radical can be substituted by pyridyl or an amino group, this amino group by two identical or different substituents from the group alkyl, Alkoxyalkyl, aryl or aralkyl is substituted, or wherein the amino group is substituted in the way is that two substituents together with the nitrogen atom form a 5- to 7-membered one Form a ring that is acidic as another heteroatom substance or sulfur or an N-alkyl / phenyl group may contain 4th R and R can be identical or different and each represents hydrogen, an achiral straight-chain or branched, optionally substi tuted alkyl radical, an aryl radical or an aralkyl radical and Le A 23 151 .3- R for hydrogen or an achiral straight chain term or branched alkyl radical, an aryl radical or an aralkyl radical, characterized in that compounds of the general formula (II) (including their prototropic forms) II 12 4 5 in which the radicals R, R, R, R and R are the above have given meaning and R stands for an alkyl or aralkyl radical and in which the configuration is uniformly defined on the carbon atoms marked with (*), with amines of the general formula (III) R ³ -NH ₂ (III) or their acid addition salts, in which R has the meaning given above, optionally reacting in the presence of suitable solvents. Le A 23 151 2. The method according to claim 1 for the preparation of compounds of general formula (I), in which R stands for a phenyl or naphthyl radical or for thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, Oxazolyl, isoxazolyl, thiazolyl, pyridyl, Pyridazinyl, pyrimidyl, pyrazinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, Benzoxadiazolyl, benzthiadiazolyl, quinolyl, isoquinolyl, quinazolyl or quinoxalyl, where the said heterocycles and the phenyl radical and the naphthyl radical 1 to 3 can carry identical or different substituents, where as Substituents phenyl, straight-chain or branched alkyl with up to 8 carbon atoms, Cycloalkyl with 3 to 7 carbon atoms, Alkenyl or alkynyl with 2 to 6 carbon atoms, alkoxy with 1 to 4 carbon atoms, Alkenoxy and alkynoxy with 2 to 6 carbon atoms, tri-, tetra- and pentamethylene, dioxymethylene, Dioxyethylidene, halogen such as fluorine, Chlorine, bromine or iodine, tri fluorine thy 1, trifluoroethyl, Trifluoromethoxy, difluoromethoxy, tetrafluoroethoxy, dialkylamino with 1 to 4 carbon atoms, Nitro, cyano, azido, alkoxycarbonyl with 1 to 4 carbon atoms in the alkoxy radical or SO -alkyl, in which m 0 or 2 and alkyl contains 1 to 4 carbon atoms, may be listed, Le A 23 151 R and R, which are always different, for an achiral straight-chain, branched or cycli ^ see saturated or unsaturated hydrocarbon residue with up to 8 carbon atoms, optionally by an oxygen or Sulfur atom in the chain is interrupted and / or which is optionally substituted by Halogen such as fluorine or chlorine, cyano, alkoxycarbonyl with up to 4 carbon atoms in the alkyl part, Phenyl, phenoxy, phenylthio or phenyl sulfonyl, it being possible for the phenyl groups in turn to be substituted by halogen such as fluorine or chlorine, cyano, dialkylamino with up to 4 carbon atoms per alkyl group, alkoxy or Alkyl with up to 4 carbon atoms each, Trifluoromethyl or nitro, or where the hydrocarbon radical can be substituted by pyridyl or an amino group, this amino group by two identical or different substituents from the group alkyl with up to 4 carbons material atoms, alkoxyalkyl with up to 6 carbon atoms, aryl, especially phenyl, or aralkyl, in particular benzyl, is substituted, or wherein the amino group is substituted in such a way that two radicals together with the nitrogen atom form a 5- to 7-membered heterocyclic ring, the further heteroatom is oxygen or sulfur or an N-alkyl / phenyl group may contain and Le A 23 151 ■ G- 2 4
R and R, can be identical or different, for hydrogen or preferably for a straight-chain or branched, optionally substituted alkyl radical with up to 4 carbon atoms, a phenyl or a benzyl rest, and R represents hydrogen or an achiral straight-chain or branched alkyl radical with up to to 4 carbon atoms, a phenyl radical or represents a benzyl radical. 3. The method according to claims 1 and 2, characterized characterized in that acid addition salts of the compounds of general formula (III) from the Group ammonium and methylammonium sulfates, chlorides, carbonates, hydrogen carbonates, acetates or oxalates are used. 4. Process according to Claims 1 to 3, characterized in that the reaction is carried out at temperatures between 0 and 150 ⁰ C and in the presence of an inert organic solvent. 5. Process according to claims 1 to 4, characterized in that the optical antipodes of the general formula (I) purifies by chromatography. Le A 23 151 6. Compounds of the general formula (II) R.
I * (ID in which R, R, R, R, R and R have the meaning given in claim 1. 7. Compounds of general formula (II) according to claim 6, in which R stands for a phenyl or naphthyl radical or for Thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, Pyridazinyl, pyrimidyl, pyrazinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, Benzoxadiazolyl, benzthiadiazolyl, quinolyl, isoquinolyl, quinazolyl or quinoxalyl, where 5 the mentioned heterocycles and the phenyl radical and the naphthyl radical 1 to 3 can carry identical or different substituents, where as Substituents phenyl, straight-chain or branched alkyl with up to 8 carbon atoms, Cycloalkyl with 3 to 7 carbon atoms, Le A 23 151 ■ S- Alkenyl or alkynyl with 2 to 6 carbon atoms, alkoxy with 1 to 4 carbon atoms, Alkenoxy and alkynoxy with 2 to 6 carbon atoms, tri-, tetra- and pentamethylene, dioxymethylene, Dioxyethylidene, halogen such as fluorine, chlorine, bromine or iodine, trifluoromethyl, trifluoroethyl, Trifluoromethoxy, difluoromethoxy, tetrafluoroethoxy, Dialkylamino with 1 to 4 carbon atoms, nitro, cyano, azido, alkoxycarbonyl with 1 to 4 C atoms in the alkoxy radical or SO -alkyl, in which m. 0 or 2 and alkyl contains 1 to 4 carbon atoms, may be listed, R and R, which are always different, for one achiral straight-chain, branched or cyclic saturated or unsaturated coals residual hydrogen with up to 8 carbon atoms, which may be interrupted by an oxygen or sulfur atom in the chain and / or which is optionally substituted by halogen such as fluorine or chlorine, cyano, alkoxy carbonyl with up to 4 carbon atoms in the alkyl part, Phenyl, phenoxy, phenylthio or phenylsulfonyl, the phenyl groups in turn can be substituted by halogen such as fluorine or chlorine, cyano, dialkylamino with up to 4 Carbon atoms per alkyl group, alkoxy or alkyl with up to 4 carbon atoms each, Trifluoromethyl or nitro, or where the carbon Le A 23 151 hydrogen radical can be substituted by pyridyl or an amino group, these Amino group by two identical or different substituents from the group alkyl with up to 4 carbon atoms, alkoxyalkyl with up to 6 carbon atoms, aryl, especially phenyl, or aralkyl, especially Benzyl, is substituted, or wherein the amino group is substituted in such a way that two radicals together with the nitrogen atom form a 5- to 7-membered heterocyclic Form ring, the further hetero atom oxygen or sulfur or an N-alkyl / phenyl grouping may contain 4th
■ J5 R and R, can be identical or different, for hydrogen or preferably for a straight-chain or branched, optionally substituted alkyl radical with up to 4 carbon atoms, a phenyl or a benzyl radical, and R for an achiral straight-chain or branched alkyl radical with up to 4 carbon atoms, especially for the methyl group or for an aralkyl radical, especially for the benzyl radical, stand. Le A 23 151 - 29 · - -ΊΟ- 8. A process for the preparation of compounds of the general formula (II) according to claim 6, characterized characterized in that an optically active hydrazone of the general formula (IV) R ⁴ ^ -C-CH ₂ -CO ₂ R ⁵ Ii (IV) in which 4 5 R, R and R have the meaning given in claim 6 to have, with stereochemically uniform prochiral ylidene-ß-ketocarboxylic acid esters of the general Formula (V) R-CH = C - (V) COR ² in which 1 2 R, R and R have the meaning given in claim 6, optionally in the presence of inert organic solvents. Le A 23 1.51 9. Use of compounds of the general formula (II) according to claim 6 in the preparation of compounds of the general formula (I) according to claim 1. Le A 23 151